INTRODUCTION

Chronic myeloid leukemia (CML) is a rare hematologic malignancy characterized by the Philadelphia chromosome (t(9;22)(q34;q11.2)), resulting in the BCR-ABL fusion gene, which drives excessive myeloid cell proliferation [1,2]. With an annual incidence of 1–2 cases per 100,000, CML accounts for approximately 0.5% of all cancers [3,4]. The advent of tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, has revolutionized CML treatment, significantly improving patient outcomes [5]. However, these therapies are associated with cardiovascular complications, notably peripheral arterial disease (PAD), which poses a significant challenge to long-term management [6].

PAD, marked by reduced blood flow to the limbs due to arterial narrowing or occlusion from atherosclerotic plaque buildup, is linked to increased morbidity and mortality [6]. Studies report a 9% prevalence of PAD in CML patients on TKI therapy, with variations depending on the specific TKI used [7]. TKIs, while effective against CML, may contribute to vascular dysfunction through mechanisms such as endothelial damage, platelet aggregation, and accelerated atherosclerosis [7,8]. Notably, nilotinib has been associated with a higher PAD incidence (30.8%) compared to imatinib (4.9%) [7]. Another study reported a 14.6-fold increased PAD risk with nilotinib versus imatinib [8].

Mechanistically, nilotinib promotes atherosclerosis by inhibiting discoidin domain receptor 1 (DDR1) and upregulating pro-atherogenic cell surface adhesion molecules [9,10]. Imatinib, targeting c-KIT, DDR1, and platelet-derived growth factor receptor (PDGF-R), may also accelerate atherosclerosis and endothelial damage [9]. Dasatinib, though less studied, is linked to pulmonary arterial hypertension in some cases [11]. These findings highlight the diverse cardiovascular risks of TKIs. In Indonesia, data on PAD prevalence in CML patients are scarce, and routine ankle-brachial index (ABI) assessments, a non-invasive measure of peripheral vascular health, are not standard. Given global variations in disease epidemiology and treatment responses, this study evaluates ABI values in CML patients treated with imatinib versus nilotinib at Adam Malik Hospital, Medan. By examining PAD prevalence and its association with TKI therapy, this research aims to provide novel insights into the cardiovascular health of CML patients in Indonesia, informing future therapeutic strategies.

METHODS

Study Design and Setting This cross-sectional analytical study was conducted at Adam Malik Hospital, Medan, Indonesia, from December 2023 to February 2024, to compare Ankle-Brachial Index (ABI) values in chronic myeloid leukemia (CML) patients treated with imatinib or nilotinib. Ethical approval was obtained from the Health Research Ethics Committee, Faculty of Medicine, Universitas Sumatera Utara.

Study Design and Setting This cross-sectional analytical study was conducted at Adam Malik Hospital, Medan, Indonesia, from December 2023 to February 2024, to compare Ankle-Brachial Index (ABI) values in chronic myeloid leukemia (CML) patients treated with imatinib or nilotinib. Ethical approval was obtained from the Health Research Ethics Committee, Faculty of Medicine, Universitas Sumatera Utara. Inclusion and Exclusion Criteria Eligible participants were CML patients aged ≥18 years receiving imatinib or nilotinib therapy. Patients with diabetes mellitus, hypertension, heavy smoking (Brinkman Index >600), prior lower limb amputation, severe peripheral arterial disease unrelated to CML therapy, significant cardiovascular conditions, or comorbidities affecting ABI were excluded to minimize confounding factors.

Table 1. ABI classifications are presented in

Notes: ABI classifications for CML patients, calculated as the ratio of highest ankle to brachial systolic pressure: Abnormal (<0.9), Borderline (0.91–0.99), Normal (1.0–1.4), Noncompressible vessels (>1.4).

After explaining the study’s objectives, procedures, and benefits, informed consent was obtained from participants. Baseline demographic data, including age, gender, residence, occupation, and phone number, were collected at the Hematology and Medical Oncology Polyclinic. Additional variables recorded included ABI scores, Brinkman Index, and history of diabetes mellitus or hypertension. Data collection involved patient observation sheets, informed consent forms, Doppler ultrasound, conductive jelly, and writing instruments. ABI measurements were performed using a standardized Doppler ultrasound device by trained researchers, with results verified by staff from the Endocrinology, Metabolism, and Diabetes Division, Department of Internal Medicine, Universitas Sumatera Utara. Following ethical clearance, consecutive sampling was employed to recruit participants. Resting ABI measurements were conducted after patients rested in a supine position for 10 minutes. Systolic pressures were measured in the brachial arteries (both arms) and dorsalis pedis and posterior tibial arteries (both legs) using Doppler ultrasound. The ABI score for each leg was calculated by dividing the highest ankle systolic pressure by the highest brachial systolic pressure

Descriptive statistics summarized demographic characteristics and frequency distributions. ABI values between imatinib and nilotinib groups were compared using inferential statistics. Independent t-tests analyzed numerical data, while chi-square tests evaluated categorical data. Fisher’s exact test was applied when chi-square assumptions were unmet. Statistical significance was set at p<0.05, with analyses conducted using appropriate statistical software to ensure systematic and accurate results.

RESULTS

Patient Characteristics This study included 48 chronic myeloid leukemia (CML) patients from the Hematology and Medical Oncology Polyclinic at Adam Malik Hospital, Medan, who fulfilled the inclusion and exclusion criteria. The sampling process is depicted in Figure 1 (placed below this paragraph). Of the participants, 62.5% (n=30) were male. Patients were allocated into two groups based on treatment: 34 (70.8%) received imatinib, and 14 (29.2%) received nilotinib. The mean age was 42.9 ± 14.9 years for the imatinib group and 49.1 ± 12.3 years for the nilotinib group. Comprehensive patient characteristics are presented in Table 1 (placed at the end of this section). No patients had diabetes mellitus, hypertension, or heavy smoking (Brinkman Index >600), minimizing potential confounders.

Figure 1. Sampling Flow

Ankle-Brachial Index (ABI) Findings In the imatinib group, 7 patients (20.6%) exhibited abnormal ABI values (<0.9), with a mean left ABI of 1.06 ± 0.11. Conversely, 7 patients (50%) in the nilotinib group had abnormal ABI values, with a significantly lower mean left ABI of 0.91 ± 0.12 (p=0.017). The median right ABI values were 1.09 (range: 0.8–1.2) for the imatinib group and 0.91 (range: 0.8–1.2) for the nilotinib group, showing no significant difference (p=0.109). These results are illustrated in Figure 2 (placed below this paragraph).

Figure 2. ABI Values in Patients Receiving Imatinib and Nilotinib

Statistical analysis confirmed a significant difference in left ABI values between the imatinib and nilotinib groups (p=0.017), indicating an elevated risk of peripheral arterial disease (PAD) in the nilotinib group. The odds ratio for abnormal ABI values was 3.857 (p=0.042), suggesting that nilotinib is associated with a higher PAD risk compared to imatinib. These findings highlight a greater propensity for vascular complications in patients treated with nilotinib.

Table 1. Characteristics of Study Participants

Note: Characteristics of CML patients on imatinib (n=34) or nilotinib (n=14) at Adam Malik Hospital, including age, gender, treatment duration, comorbidities, and ABI values. Independent t-tests and chi-square tests assessed differences (p<0.05). No patients had diabetes, hypertension, or heavy smoking (Brinkman Index >600). Left ABI significantly lower in nilotinib group (p=0.017).

The results demonstrate that CML patients receiving nilotinib exhibit a significantly higher risk of PAD, as indicated by lower left ABI values, compared to those on imatinib. The elevated prevalence of abnormal ABI in the nilotinib group underscores the necessity for rigorous cardiovascular monitoring in these patients.

DISCUSSION

Chronic myeloid leukemia (CML) arises from the Philadelphia chromosome, a translocation between chromosomes 9 and 22, resulting in the BCR-ABL1 fusion gene, which drives uncontrolled myeloid cell proliferation [12,13]. Tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, target this fusion gene and have transformed CML management [14]. This study focused on the cardiovascular implications of imatinib and nilotinib, specifically their association with peripheral arterial disease (PAD), assessed through Ankle-Brachial Index (ABI) measurements in 48 CML patients at Adam Malik Hospital, Medan.

Of the 48 patients, 34 received imatinib and 14 received nilotinib, with mean ages of 42.9 ± 14.9 and 49.1 ± 12.3 years, respectively (p=0.639). Gender distribution was comparable (imatinib: 64.7% male; nilotinib: 57.1% male, p=0.623), and treatment duration showed no significant difference (p=1.000). These findings align with Nunes et al., who reported similar gender distributions in TKI-treated CML patients [10]. However, the younger mean age in our study compared to Rattanathammethee et al. (54 and 68 years for imatinib and nilotinib groups, respectively) may reflect regional demographic differences [7]. The study revealed a significantly higher prevalence of abnormal ABI values (<0.9) in the nilotinib group (50%) compared to the imatinib group (20.6%), with a mean left ABI of 0.91 ± 0.12 versus 1.06 ± 0.11 (p=0.017). The odds ratio for abnormal ABI was 3.857 (p=0.042), indicating a greater PAD risk with nilotinib. These results corroborate Rattanathammethee et al., who reported a 30.8% PAD prevalence in nilotinib-treated patients versus 4.9% in imatinib-treated patients [7]. Similarly, a retrospective study of 3,722 CML patients found higher cardiovascular risks with nilotinib, even after adjusting for baseline risk factors [10].

Mechanistically, nilotinib’s higher BCR-ABL1 affinity may enhance its efficacy but also its cardiovascular toxicity [14]. Nilotinib upregulates pro-atherogenic markers, including thrombin, TNF-α, IL-6, and adhesion molecules (P-selectin, E-selectin, ICAM1, VCAM1), potentially increasing PAD risk [10]. It also elevates blood glucose and LDL cholesterol, further promoting atherosclerosis [10]. Imatinib, while less cardiotoxic, inhibits DDR1, PDGF-R, and c-KIT, which may still contribute to endothelial damage and atherosclerosis [9]. These mechanisms likely underlie the observed ABI differences.

The findings emphasize the need for routine cardiovascular monitoring in CML patients on TKIs, particularly nilotinib. Pre-treatment and follow-up assessments, including blood pressure, lipid profiles, fasting glucose, ECG, echocardiography, and ABI, are recommended at baseline, 1-month, 3–6 months, and periodically thereafter [15-17]. Despite its efficacy, nilotinib’s cardiovascular risks necessitate careful patient selection, considering factors like age and comorbidities. Limitations include the small nilotinib group size (n=14), single-center design, and potential unadjusted confounders like age. Nevertheless, this study highlights the importance of tailored TKI therapy to balance efficacy and safety. Future research should explore strategies to mitigate nilotinib’s cardiovascular risks and evaluate alternative TKIs for long-term CML management.

CONCLUSION

This study reveals a significant association between tyrosine kinase inhibitor therapy and peripheral arterial disease risk in chronic myeloid leukemia patients, with nilotinib linked to a higher prevalence of abnormal Ankle-Brachial Index values (50%) compared to imatinib (20.6%, p=0.042, odds ratio 3.857). These findings emphasize the need for tailored cardiovascular monitoring, particularly for nilotinib-treated patients, to reduce vascular complications. Optimizing TKI selection based on patient risk profiles is critical to balance efficacy and safety in CML management.

DECLARATIONS

None

CONSENT FOR PUBLICATION

The Authors agree to be published in the Journal of Society Medicine.

FUNDING

None

COMPETING INTERESTS

The authors declare no conflicts of interest in this case report.

AUTHORS’ CONTRIBUTIONS

All authors contributed to the work, including data analysis, drafting, and reviewing the article. They approved the final version and were accountable for all aspects.

ACKNOWLEDGMENTS

None

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